Structure of the HIV-1 nucleocapsid protein bound to the SL3 Ψ-RNA recognition element

The three-dimensional structure of the human immunodeficiency virus-type 1 (HIV-1) nucleocapsid protein (NC) bound to the SL3 stem-loop recognition element of the genomic Psi RNA packaging signal has been determined by heteronuclear magnetic resonance spectroscopy. Tight binding (dissociation constant, similar to 100 nM) is mediated by specific interactions between the amino-and carboxyl-terminal CCHC-type zinc knuckles of the NC protein and the G(7) and G(9) nucleotide bases, respectively, of the G(6)-G(7)-A(8)-G(9) RNA tetraloop. A(8) packs against the amino-terminal knuckle and forms a hydrogen bond with conserved Arg(32), and residues Lys(3) to Arg(10) of NC form a 3(10) helix that binds to the major groove of the RNA stem and also packs against the amino-terminal zinc knuckle. The structure provides insights into the mechanism of viral genome recognition, explains extensive amino acid conservation within NC, and serves as a basis for the development of inhibitors designed to interfere with genome encapsidation.